The NEAT Study: A 48-Week Open-Label Study to Compare the Antiviral Efficacy and Safety of GW433908 Versus Nelfinavir in Antiretroviral Therapy–Naive HIV-1-Infected Patients

Poor tolerability is a major cause of nonadherence and treatment discontinuation with protease inhibitors (PIs). Gastrointestinal (GI) disturbances are often cited as affecting PI tolerability, but other adverse effects, such as those that affect patient appearance or self-perception, can also negatively impact patient acceptance and adherence to or continuation of therapy. Long-term complications-such as lipodystrophy, hyperlipidemia, and insulin resistance-can deter patients from beginning therapy or discourage them from continuing therapy once it is begun. Data regarding these issues in the context of older PIs have helped define the limitations of these first-generation agents, but addressing concerns of the safety and tolerability associated with newer PIs is critical to ensuring the continued viability of the class. The new PIs atazanavir (ATV) and fosamprenavir (FPV; formerly GW-433908, or 908) have each been shown to offer improved GI tolerability and favorable lipid profiles. However, each is associated with unique traits of safety and tolerability that may differentially affect their clinical utility. Less is known about the safety and tolerability profiles of two newer PIs, tipranavir (TPV) and TMC-114, although both of these agents have shown promising results in PI-experienced patients to date. Improved safety and tolerability are important goals for the development of new PIs, which, if met, may lead to increased utilization of PIs in the management of HIV infection. This article summarizes the limitations that have been associated with PI-including therapy over the past several years and outlines how newer PIs may shape management schemes for those living with HIV infection through improved safety and tolerability.